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J. Biol. Chem., Vol. 280, Issue 37, 32272-32278, September 16, 2005

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MEF2-dependent Recruitment of the HAND1 Transcription Factor Results in Synergistic Activation of Target Promoters^*

Steves Morin1, Gina Pozzulo, Lynda Robitaille, Jay Cross¶, and Mona Nemer||2

From the Laboratory of Cardiac Growth and Differentiation, Institut de Recherches Cliniques de Montréal (IRCM), Montréal, Quebec H2W 1R7, Canada, ^||Département de Pharmacologie, Université de Montréal, Montréal, Quebec H3C 3J7, Canada, and ^¶Department of Biochemistry and Molecular Biology, University of Calgary, Health Sciences Centre, Calgary, Alberta T2N 4N1, Canada

HAND proteins are tissue-restricted members of the basic helix-loop-helix transcription factor family that play critical roles in cell differentiation and organogenesis including placental, cardiovascular, and craniofacial development. Nevertheless, the molecular basis underlying the developmental action of HAND proteins remains undefined. Within the embryo, HAND1 is first detected in the developing heart where it becomes restricted to the atrial and left ventricular compartments, a pattern identical to that of the Nppa gene, which encodes atrial natriuretic factor, the major secretory product of the heart. We hereby report that the cardiac atrial natriuretic factor promoter is directly activated by HAND1, making it the first known HAND1 transcriptional target. The action of HAND1 does not require heterodimerization with class I basic helix-loop-helix factors or DNA binding through E-box elements. Instead, HAND1 is recruited to the promoter via physical interaction with MEF2 proteins. MEF2/HAND1 interaction results in synergistic activation of MEF2-dependent promoters, and MEF2 binding sites are sufficient to mediate this synergy. MEF2 binding to DNA is not enhanced in the presence of HAND1. Instead, cooperativity likely results from corecruitment of co-activators such as CREB-binding protein. The related HAND2 protein can also synergize with MEF2. Thus, HAND proteins act as cell-specific developmental co-activators of the MEF2 family of transcription factors. These findings identify a novel mechanism for HAND action in the heart and provide a general paradigm to understand the mechanism of HAND action in organogenesis.

Received for publication, July 14, 2005

^* This work was supported by Canadian Institutes of Health Research Grant MT13057. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Recipient of a Canadian Institutes of Health Research studentship.

² Canada Research Chair in Cardiovascular Cell Differentiation. To whom correspondence should be addressed: Laboratory of Cardiac Growth and Differentiation, Institut de Recherches Cliniques de Montréal (IRCM), 110 avenue des Pins Ouest, Montréal, QC H2W 1R7, Canada. Tel.: 514-987-5680; Fax: 514-987-5575; E-mail: mona.nemer{at}ircm.qc.ca.

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